Homologous Mutation to Human BRAF V600E Is Common in Naturally Occurring Canine Bladder Cancer—Evidence for a Relevant Model System and Urine-Based Diagnostic Test

Abstract

Targeted cancer therapies offer great clinical promise, but treatment resistance is common, and basic research aimed at overcoming this challenge is limited by reduced genomic and biological complexity in artificially induced rodent tumors compared to their human counterparts. Animal models that more faithfully recapitulate genotype-specific human pathology could improve the predictive value of these investigations. Here, a newly identified animal model for oncogenic BRAF-driven cancers is described. With 20,000 new cases in the United States each year, canine invasive transitional cell carcinoma of the bladder (InvTCC) is a common, naturally occurring malignancy that shares significant histological, biological, and clinical phenotypes with human muscle invasive bladder cancer. In order to identify somatic drivers of canine InvTCC, the complete transcriptome for multiple tumors was determined by RNAseq. All tumors harbored a somatic mutation that is homologous to the human BRAF(V600E) mutation, and an identical mutation was present in 87% of 62 additional canine InvTCC tumors. The mutation was also detectable in the urine sediments of all dogs tested with mutation-positive tumors. Functional experiments suggest that, like human tumors, canine activating BRAF mutations potently stimulate the mitogen activated protein kinase (MAPK) pathway. Cell lines with the mutation have elevated levels of phosphorylated MEK, compared to a line with wild type BRAF. This effect can be diminished through application of the BRAF(V600E) inhibitor vemurafenib. These findings set the stage for canine InvTCC as a powerful system to evaluate BRAF-targeted therapies, as well as therapies designed to overcome resistance, which could enhance treatment of both human and canine cancers

A pilot study of toceranib/vinblastine therapy for canine transitional cell carcinoma

“…Based on inter-operator variability and the lack of correlation between clinical outcome and imaging, clinical decision-making based upon image findings alone is not recommended. Alternative measures of disease burden, including activating BRAF mutations, survivin and telomerase activity have also been evaluated in TCC [48–51]. …”

Concise Review: Stem Cell Trials Using Companion Animal Disease Models

“…Companion animal diseases mirror many human conditions with respect to their symptoms, natural history, pathology, gene associations, molecular phenotype, environmental risk factors, and responses to medication [6]. Homology of gene sequences in healthy tissues and tumors is more extensive between humans and companion animals (e.g., dogs and cats), than between humans and rodents [7][8][9][10][11][12]. The epigenomic behavior (e.g., DNA methylation) of canine and human tumor cells strongly resembles each other [13][14][15][16].…”

Glutathione S‐transferase theta genotypes and environmental exposures in the risk of canine transitional cell carcinoma

“…Dogs with TCC were recruited from the University of Wisconsin‐Madison and from Purdue University, and through collaborations with Colorado State University, the University of Georgia, Texas A&M University, and several private veterinary oncology and primary care practices. The diagnosis of TCC was based on visualization of a bladder or urethral mass on abdominal ultrasound or cystoscopy, combined with positive urine cytology, bladder histopathology, or the BRAF (Raf family serine/threonine‐protein kinase B gene) mutation detection in voided urothelial cells . Confirmed TCC cases could be of any breed, sex, or age.…”